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1.
Am J Med Genet A ; 161A(8): 2004-8, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23824684

ABSTRACT

Interstitial duplication of the long arm of chromosome 12 is a rare cytogenetic condition. While several reports describe distal 12q duplication, only one case report of homogeneous, non-mosaic interstitial 12q13 duplication has been documented to date. The authors of that observation proposed that the associated phenotype represented a phenocopy of Wolf-Hirschhorn syndrome [Dallapiccola et al., 2009]. Only a few other recorded patients with deletion 12q13 → 12q21 involved mosaicism. We describe a new patient with homogeneous 12q13 duplication in a 6-year-old girl who, in early infancy, presented with dysmorphic features suggesting Wolf-Hirschhorn syndrome. What is potentially significant about this patient is that her facial phenotype evolved with age, suggesting a different gestalt in older patients.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 12/genetics , Wolf-Hirschhorn Syndrome/genetics , Child , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Phenotype , Review Literature as Topic , Wolf-Hirschhorn Syndrome/pathology
3.
Neurology ; 78(10): 690-5, 2012 Mar 06.
Article in English | MEDLINE | ID: mdl-22323755

ABSTRACT

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.


Subject(s)
Huntington Disease/genetics , Trinucleotide Repeat Expansion , Adult , Age of Onset , Alleles , Female , Genotype , Humans , Huntington Disease/diagnosis , Male
4.
Neurology ; 74(10): 839-45, 2010 Mar 09.
Article in English | MEDLINE | ID: mdl-20211908

ABSTRACT

BACKGROUND: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases. METHODS: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events. RESULTS: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8-147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2-364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (-7.05 [4.96] vs 0.16 [2.65]) and major subscores (-2.11 [2.75] vs 0.68 [1.94] for static function, -4.11 [2.96] vs 0.37 [2.0] for kinetic function, and -0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred. CONCLUSIONS: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%-79.9%).


Subject(s)
Cerebellar Ataxia/drug therapy , Neuroprotective Agents/therapeutic use , Riluzole/therapeutic use , Adult , Aged , Confidence Intervals , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pilot Projects , Severity of Illness Index , Young Adult
6.
Cytogenet Genome Res ; 100(1-4): 147-53, 2003.
Article in English | MEDLINE | ID: mdl-14526175

ABSTRACT

Spinocerebellar ataxia type 6 (SCA6) is one of three allelic disorders caused by mutations of CACNA1A gene, coding for the pore-forming subunit of calcium channel type P/Q. SCA6 is associated with small expansions of a CAG repeat at the 3' end of the gene, while point mutations are responsible for its two allelic disorders (Episodic Ataxia type 2 and Familial Hemiplegic Migraine). Genetic, clinical, pathological and pathophysiological data of SCA6 patients are reviewed and compared to those of other SCAs with expanded CAG repeats as well as to those of its allelic channelopathies, with particular reference to Episodic Ataxia type 2. Overall SCA6 appears to share features with both types of disorders, and the question as to whether it belongs to polyglutamine disorders or to channelopathies remains unanswered at present.


Subject(s)
Ataxia/genetics , Calcium Channels/genetics , Spinocerebellar Ataxias/genetics , Alleles , Ataxia/pathology , Humans , Point Mutation , Spinocerebellar Ataxias/pathology , Trinucleotide Repeat Expansion/genetics
7.
Am J Med Genet A ; 119A(3): 279-82, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12784292

ABSTRACT

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.


Subject(s)
Huntington Disease/genetics , Trinucleotide Repeats , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , Humans , Middle Aged , New England , Probability , Survival Rate
8.
Brain Res Bull ; 56(3-4): 227-31, 2001.
Article in English | MEDLINE | ID: mdl-11719255

ABSTRACT

Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3' end of the CACNA1A gene, coding for the alpha(1A) subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.


Subject(s)
Calcium Channels/genetics , Glutamine/genetics , Spinocerebellar Ataxias/genetics , Trinucleotide Repeat Expansion , Calcium Channels/chemistry , Calcium Channels, N-Type/chemistry , Calcium Channels, N-Type/genetics , Humans , Spinocerebellar Ataxias/etiology
9.
Neurol Sci ; 22(1): 95-6, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11487218

ABSTRACT

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion. Three PTD loci (DYT1, DYT6 and DYT7) have been identified to date. However, in several PTD families linkage to the known loci has been excluded. We identified an Italian PTD family with 11 definitely affected members. Phenotype was characterised by juvenile or early-adult onset, prominent cranial-cervical and upper limb involvement, mild course and occasional generalisation. A genome-wide search performed in the family identified a novel PTD locus (DYT13) within a 22-cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 (theta = 0) between the disease and marker D1S2667.


Subject(s)
Chromosomes, Human, Pair 1/genetics , Dystonia Musculorum Deformans/genetics , Point Mutation/genetics , Adolescent , Adult , Age of Onset , Arm/innervation , Arm/physiopathology , Child , Child, Preschool , Chromosome Mapping , DNA Mutational Analysis , Female , Genotype , Humans , Italy , Male , Neck/innervation , Neck/physiopathology , Phenotype
10.
Ann Neurol ; 49(3): 362-6, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11261511

ABSTRACT

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial-cervical and upper limb involvement and mild severity. A genome-wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667.


Subject(s)
Chromosomes, Human, Pair 1/genetics , Dystonic Disorders/genetics , Genetic Linkage/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Mapping , Female , Haplotypes , Humans , Italy , Lod Score , Male , Pedigree
11.
Am J Hum Genet ; 68(4): 895-900, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11254447

ABSTRACT

The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.


Subject(s)
Chromosomes, Human, Pair 1/genetics , Genes, Recessive/genetics , Genetic Linkage/genetics , Ligases , Parkinsonian Disorders/epidemiology , Parkinsonian Disorders/genetics , Ubiquitin-Protein Ligases , Adult , Age of Onset , Chromosome Mapping , Female , Genetic Heterogeneity , Genetic Markers/genetics , Haplotypes/genetics , Homozygote , Humans , Italy , Lod Score , Male , Middle Aged , Parkinsonian Disorders/physiopathology , Pedigree , Phenotype , Proteins/genetics
12.
Am J Hum Genet ; 68(3): 759-64, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11179022

ABSTRACT

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha(1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha(1A-2) subunit, together with human beta(4) and alpha(2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.


Subject(s)
Calcium Channels/genetics , Cerebellar Ataxia/genetics , Chromosomes, Human, Pair 19 , Mutation, Missense , Amino Acid Sequence , Calcium Channels/chemistry , Calcium Channels/physiology , Calcium Channels, P-Type/genetics , Calcium Channels, Q-Type/genetics , Cell Line , Cerebellar Ataxia/classification , Chromosome Mapping , Female , Humans , Male , Membrane Potentials/physiology , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Patch-Clamp Techniques , Pedigree , Protein Structure, Secondary , Protein Subunits , Transfection
15.
Am J Med Genet ; 95(4): 366-73, 2000 Dec 11.
Article in English | MEDLINE | ID: mdl-11186892

ABSTRACT

We analyzed the data on age at onset and CAG size of 319 patients clinically diagnosed with Huntington disease (HD) and 86 presymptomatic subjects recorded by four Italian Centers over the last 14 years. To overcome the problem of different CAG numbers found in each subject, also in the same family, the data were analyzed in terms of deviations from the average exponential relationship between onset and CAG number. The subject's year of birth was also considered to quantify possible sampling biases. Observations between relatives were compared with those of the whole group. The deviations were equal, on average, in subjects who inherited their HD gene from their fathers or mothers. Overall, our data argue in favor of a greater similarity across the same generation than across successive generations. In particular, an excess of parents with later than expected age of onset was observed, paralleled by a CAG-independent anticipation of onset in parent-child transmissions. These results can be interpreted in terms of a shared environment determining similar departures from the average CAG-onset relationship but also of a systematic effect that differentiates the two generations here examined.


Subject(s)
Huntington Disease/epidemiology , Huntington Disease/genetics , Trinucleotide Repeat Expansion/genetics , Adolescent , Adult , Age of Onset , Bias , Confidence Intervals , Humans , Individuality , Middle Aged , Nuclear Family , Predictive Value of Tests , Regression Analysis
16.
Community Genet ; 3(4): 175-8, 2000.
Article in English | MEDLINE | ID: mdl-11878343

ABSTRACT

The need for genetic counselling derives from the peculiarities of genetic information, as compared to other biomedical tests, with particular reference to (a) its predictive character; (b) the existing gap between the ability to diagnose and to treat an inherited disorder, and (c) the psychological, social and ethical problems that genetic testing can raise. Counselling is traditionally performed by healthcare professionals, specifically trained to help individuals to develop ways of dealing with genetic information and gain a better understanding of the problems related with it. The growing number of genetic tests (for rare Mendelian as well as for common disorders), the development of easier and cheaper molecular techniques, the increasing tendency of physicians to have recourse to genetic tests, by-passing alternative diagnostic procedures, are all factors that contribute to the vast increase in the demand for genetic tests, a demand which is significantly out of step with the available numbers of trained counsellors. This paper discusses possible solutions, including the institution of committees with regulatory powers on genetic testing, the promotion of studies on models of genetic services, on programmes to monitor the services currently offered by test providers, and the expansion of training programmes and of employment opportunities for genetic counsellors.


Subject(s)
Health Personnel , Genetic Counseling/economics , Genetic Diseases, Inborn , Genetic Privacy , Genetic Testing , Humans
17.
Gene ; 241(1): 45-50, 2000 Jan 04.
Article in English | MEDLINE | ID: mdl-10607897

ABSTRACT

The P/Q-type Ca(2+) channel alpha(1A) subunit gene (CACNA1A) was cloned on the short arm of chromosome 19 between the markers D19S221 and D19S179 and found to be responsible for Episodic Ataxia type 2, Familial Hemiplegic Migraine and Spinocerebellar Ataxia type 6. This region was physically mapped by 11 cosmid contigs spanning about 1. 4Mb, corresponding to less than 70% of the whole region. The cosmid contig used to characterize the CACNA1A gene accounted only for the coding region of the gene lacking, therefore, the promoter and possible regulation regions. The present study improves the physical map around and within the CACNA1A by giving a complete cosmid or BAC contig coverage of the D19S221-D19S179 interval. A number of new STSs, whether polymorphic or not, were characterized and physically mapped within this region. Four ESTs were also assigned to cosmids belonging to specific contigs.


Subject(s)
Calcium Channels/genetics , Chromosomes, Human, Pair 19 , Contig Mapping , Blotting, Southern , Cloning, Molecular , Cosmids , Expressed Sequence Tags , Gene Library , Genetic Markers , Humans , In Situ Hybridization, Fluorescence , Models, Genetic , Sequence Tagged Sites
18.
Mov Disord ; 14(5): 820-5, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10495044

ABSTRACT

A white Italian family affected by primary torsion dystonia (PTD) is described. The family phenotype most commonly presented with adult onset, cranial cervical involvement, and focal or segmental distribution without progression to generalization. Thirty-nine family members and nine spouses were studied. Five subjects received a diagnosis of definite PTD, three of probable PTD. Age at onset was in adulthood for all. In four definitely affected subjects, dystonia started in the cranial or cervical districts; in one it presented as writer's cramp. Familial writer's cramp also occurred in the family of the unrelated parent of the latter patient. The mean age at time of examination was 61.8 years in the individuals with a definite diagnosis; 60 in those with a probable diagnosis. At the time of examination, in most of the affected subjects, dystonia was focal; in three cases (two definitely and one probably affected), it was segmental. DNA linkage analysis, although limited by the size of the family, suggested exclusion of linkage between the disease and known PTD loci (DYT6 and DYT7). The GAG deletion in the DYT1 gene was excluded in the proband and in the family member affected by writer's cramp.


Subject(s)
Cervical Vertebrae/physiopathology , Chromosomes, Human, Pair 18/genetics , Chromosomes, Human, Pair 8/genetics , Dystonic Disorders/genetics , Dystonic Disorders/physiopathology , Adult , Aged , Aged, 80 and over , Chromosome Aberrations/genetics , Chromosome Disorders , DNA Mutational Analysis , Female , Gene Expression/genetics , Genetic Linkage , Humans , Italy , Male , Microsatellite Repeats/genetics , Middle Aged , Pedigree , Point Mutation/genetics , Polymerase Chain Reaction/methods , Skull
19.
Philos Trans R Soc Lond B Biol Sci ; 354(1386): 1089-94, 1999 Jun 29.
Article in English | MEDLINE | ID: mdl-10434311

ABSTRACT

Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG)n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG)n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG)n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the alpha 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.


Subject(s)
Calcium Channels/genetics , Cerebellar Ataxia/genetics , Huntington Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Spinocerebellar Degenerations/genetics , Trinucleotide Repeat Expansion/genetics , Ataxin-1 , Ataxins , Calcium Channels/chemistry , Colonic Neoplasms/genetics , Female , Genetic Variation , Humans , Huntingtin Protein , Male , Models, Molecular , Pedigree , Peptides/genetics , Protein Structure, Secondary
20.
J Neurol Neurosurg Psychiatry ; 67(3): 395-7, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10449567

ABSTRACT

A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative efforts will be required to identify these, and additional genes, causing PTD.


Subject(s)
Chromosomes, Human, Pair 18/genetics , Chromosomes, Human, Pair 8/genetics , Dystonia Musculorum Deformans/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Chromosome Mapping , Genetic Linkage/genetics , Genetic Markers , Humans , Infant , Middle Aged
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